Nature Communications [IFM]

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The IFM team in collaboration with researchers at ENS Lyon and Institut Pasteur used advanced molecular simulations to investigate how cannabinoids bind to glycine receptors, an important pharmacological target for chronic pain. They discovered that tetrahydrocannabinol (THC) and anandamide (AEA) bind to more than one region of the receptor's transmembrane domain and characterized their binding mode with atomic resolution. The results demonstrate that coarse-grained simulations have come to age and provide straightforward access to the recognition of allosteric ligands at transmembrane protein domains. These results have appeared in Nature Communications.

Abstract:

Glycine receptors (GlyR) are regulated by small-molecule binding at several allosteric sites. Cannabinoids like tetrahydrocannabinol (THC) and N-arachidonyl-ethanol-amide (AEA) potentiate the GlyR response but their mechanism of action is not fully established. By combining millisecond coarse- grained (CG) MD simulations powered by Martini 3 with backmapping to all-atom representations, we have characterized the cannabinoid-binding site(s) at the zebrafish GlyR-α1 active state with atomic resolution. Based on hundreds of thousand ligand-binding events, we find that cannabinoids bind to the transmembrane domain of the receptor at both intrasubunit and intersubunit sites. For THC, the intrasubunit binding mode predicted in simulation is in excellent agreement with recent cryo-EM structures, while intersubunit binding recapitulates in full previous mutagenesis experiments. Intriguingly, AEA is predicted to bind at the same intersubunit site despite the strikingly different chemistry. Statistical analyses of the ligand-receptor interactions highlight potentially relevant residues for GlyR potentiation, offering experimentally testable predictions. The predictions for AEA have been validated by electrophysiology recordings of rationally designed mutants. The results highlight the existence of multiple cannabinoid-binding sites for the allosteric regulation of GlyR and establish an effective strategy for the identification and structural characterization of allosteric binding sites.

 

Reference :

A millisecond coarse-grained simulation approach to decipher allosteric cannabinoid binding at the glycine receptor α1

Alessio Bartocci, Andrea Grazzi, Nour Awad, Pierre-Jean Corringer, Paulo C. T. Souza & Marco Cecchini

Nature Communications 15, 9040 (2024), DOI: https://doi.org/10.1038/s41467-024-53098-4

Contact :

Marco Cecchini, équipe IFM, Institut de Chimie de Strasbourg (UMR 7177).